The alkaloids obtainable from Vinca rosea represent one of the most productive sources of drugs which adversely affect the growth of experimental malignancies in mammals. Initially, only some of the alkaloids obtainable from the leaves of the plant by extraction and chromatography were found to be active as oncolytic agents. These active anti-neoplastic vinca alkaloids obtained directly from the plant have all turned out to be dimeric indole-dihydroindole alkaloids representable by the formula: ##STR1##
In the above formula, where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is hydroxyl, R.sup.4 is ethyl and R.sup.5 is H, VLB (vincaleucoblastine, vinblastine) is represented; where R.sup.1 is acetoxy, R.sup.2 is formyl, R.sup.3 is hydroxyl, R.sup.4 is ethyl and R.sup.5 is H, vincristine (VCR, leurocristine) is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is ethyl, R.sup.4 is hydroxyl, and R.sup.5 is H, leurosidine (vinrosidine) is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is ethyl, and R.sup.4 and R.sup.5 are H, 4'-deoxyleurosidine (deoxy VLB"B") is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.4 is ethyl and R.sup.3 and R.sup.5 are H, 4'-deoxy VLB (deoxy VLB"A") is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl or formyl, R.sup.3 is ethyl and R.sup.4 and R.sup.5 taken together with a bridging oxygen form an .alpha.-epoxide ring, leurosine (vinleurosine), and formylleurosine (leuroformine), respectively, are represented. Literature references to the above alkaloids are as follows: leurosine (U.S. Pat. No. 3,370,057), VLB (U.S. Pat. No. 3,097,137), formylleurosine (leuroformine) (U.S. Pat. No. 4,189,432); leurosidine and leurocristine (both in U.S. Pat. No. 3,205,220), and deoxy VLB"A" and "B", Tetrahedron Letters, 783 (1968).
Two of the above alkaloids, VLB and vincristine, are now marketed for the treatment of malignancies, particularly the leukemias and related diseases in humans. The two marketed alkaloids are customarily administered by the i.v. route. Two others, leurosidine and formylleurosine, have been on clinical trial, either in the U.S. or in Europe.
VLB is more abundant than vincristine, being isolatable in usually eight to ten-fold greater quantities. Methods of converting VLB to vincristine are therefore highly desirable, and much research time and considerable resources have been expended looking for such procedures.
As is the case with the pair VLB-vincristine, the pair leurosine-formylleurosine is characterized by the greater abundance of the N-methyl derivative--leurosine--in the crude alkaloid mixture obtained from Vinca rosea leaves. Use of formylleurosine in treating lymphoid leukemia, lymphoma, Hodgkin's disease and multiple myeloma are claimed in U.S. Pat. Nos. 4,279,916, 4,279,915 and 4,279,816.
To date, only three methods of converting VLB to vincristine have appeared in the literature. These are: enzymatic oxidation with a peroxidase and H.sub.2 O.sub.2, (Gorman-U.S. Pat. No. 3,354,163); catalytic oxidation with molecular oxygen at ambient temperature in formic acid (Derwent Abstract No. 33812Y/19 based on Soviet Union Pat. No. 521,845); and oxidation of VLB sulfate with chromic oxide in glacial acetic acid and acetone at -60.degree. C. (U.S. Pat. No. 3,899,943). Vincristine yields of 50% based on recovered VLB are reported by the latter procedure.
The published procedures for producing formylleurosine by oxidation of leurosine or for producing 4'-deoxy-1-desmethyl-1-formylleurosidine by oxidation of 4'-deoxyleurosidine both involve a low temperature (-60.degree. C.) process utilizing the CrO.sub.3, acetone and acetic acid oxidation mixture first found useful for producing vincristine from VLB.
This chromic acid--acetone--acetic acid oxidation process at -60.degree. C. is not without drawbacks, however. The maintenance of low reaction temperatures is difficult in a manufacturing plant, but higher temperatures produce increasing quantities of undesirable by-products. In addition, Barnett et al., U.S. Pat. No. 4,110,330, have found that, in the VLB-vincristine conversion, VLB reacts with acetone at C-5' under oxidizing conditions, even at -60.degree. C., to yield 5'-acetonylvincristine and related products. Similar 5'-substitution products are produced in oxidizing leurosine or 4'-deoxyleurosidine with this oxidizing system.
These undesirable 5'-VCR derivatives encountered as by-products in the chromic acid oxidation of VLB sulfate in acetone are definite detriments to the use of that process in manufacturing vincristine from VLB. The 5'-acetonyl compounds are, of course, separable from vincristine by chromatography, but there is a consequent loss of the desired product, vincristine. Furthermore, during this oxidation, there are produced substantial quantities of N-desformyl vincristine which must be reformylated in order to maximize vincristine yields. Reformylation is an added, expensive procedure when oxidation results in deformylation as well as oxidation.
It is an object of this invention to provide a procedure for converting VLB, leurosine, 4'-deoxyleurosidine, 4-desacetyl VLB and related N-methyl vinca dimers to their respective vincristine-type compounds, which procedure avoids the drawbacks of the prior art procedures.